Phlebotomy improves therapeutic response to interferon in patients with chronic hepatitis C: a meta-analysis of six prospective randomized controlled trials

Desai T K, Jamil L H, Balasubramaniam M, Koff R, Bonkovsky H L

CRD summary

The authors concluded that phlebotomy appeared to enhance the efficacy of non-pegylated interferon monotherapy for chronic hepatitis C, but more research was required. The reported data appeared to support these conclusions, but limitations in review methods and the suboptimal quality of the primary studies suggest that the findings should be interpreted with caution.

Authors' objectives

To evaluate the use of phlebotomy with interferon (IFN) versus interferon alone in patients with chronic hepatitis C (CHC).

Searching

MEDLINE (1992 to 2005) and the Cochrane Library were searched and search terms were provided. The reference lists of relevant studies and reviews were checked. Authors of potentially eligible studies were contacted for information about any additional studies.

Study selection

Randomised controlled trials (RCTs) comparing IFN after therapeutic phlebotomy with IFN alone were eligible for inclusion, provided that SVR was reported as an outcome and that an intention-to-treat (ITT) analysis was possible.

Most patients in the included studies were genotype one (53 per cent to 100 per cent), 78 per cent were male and in most studies all participants were previously untreated. Some studies included only patients with high iron stores. In one study all participants had concomitant porphyria cutanea tarda. Half the studies (comprising nearly 75 per cent of the total review sample) excluded patients with cirrhosis. In most cases IFN was administered three times weekly for six to 12 months (where stated). Most studies used non-pegylated IFN, but one used pegylated iron in combination with daily ribavirin. The phlebotomy protocol was administered every one or two weeks. Iron depletion (for example, ferritin under 10-15 nanograms per millilitre (ng/ml)) was induced in the majority of studies; the sixth study had a more conservative target threshold (ferritin under 100 ng/ml). In addition to SVR, the review reported liver histology as an outcome (comparison of before and after liver biopsy samples), using various measures including the Knodell score.

The authors did not state how the papers were selected for the review nor how many reviewers performed the selection.

Assessment of study quality

Study validity was assessed using the Jadad scale, which measures adequacy of randomisation, blinding and the management of withdrawals and dropouts. The authors did not state how the validity assessment was performed.

Data extraction

Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated from the numbers of events in each group. Data were extracted independently by three reviewers. Descriptive data were reported for the outcome of liver histology.

Methods of synthesis

Odds ratios were pooled to obtain Peto odds ratios with 95% confidence intervals (CIs). Heterogeneity was assessed using the Χ2 test and I2 statistic. Sensitivity analyses were performed to examine the effect of removing individual studies from analysis. It was planned to assess small study/publication bias if there were 10 or more included studies.

Results of the review

Six RCTs were included (n=367); five were fully published and one was in abstract form. Three were considered to have described an adequate method of generating the sequence of randomisation. None reported any form of blinding. Two RCTs reported using ITT analysis and the other four provided sufficient details about follow-up and dropouts to permit ITT analysis. Three of the studies scored a total of three Jadad points and three scored three points (out of a possible five). Sensitivity analysis did not alter the statistical significance of the results.

Paired liver biopsy samples were obtained in all patients in only one RCT (n=30), which reported significant histological improvement from baseline (by Knodell score) in the intervention group, but not in the control group.

Authors' conclusions

Phlebotomy appeared to enhance the efficacy of non-pegylated IFN monotherapy for CHC, but more research was required to confirm this.

CRD commentary

The objectives and inclusion criteria of the review were clear in most respects, though sustained viral response (SVR) was not defined. Two relevant databases were searched, but as no specific attempt to retrieve unpublished studies was reported it is possible that some studies were missed. It was not stated whether the search was restricted by language. Data were extracted independently by more than one reviewer, but it was not stated whether similar precautions were taken when selecting studies and assessing study validity. Jadad scores were reported, but no details were provided on aspects of study validity such as allocation concealment and dropout rates. Appropriate statistical methods were used to pool studies and to assess for heterogeneity. Small study/publication bias was not assessed. Problems associated with the limited volume of data and clinical and methodological heterogeneity between the studies were acknowledged and addressed in the discussion section of the review. The doubtful applicability of evidence relating to non-pegylated IFN was also highlighted. The data reported were consistent and appeared to support the authors’ conclusions, but limitations in review methods and the suboptimal quality of the primary studies suggest that the findings should be interpreted with caution.

Implications of the review for practice and research

Practice: the authors did not state any implications for practice.

Research: the authors stated that adequately powered RCTs with detailed pre-treatment iron studies should be considered to evaluate phlebotomy as an adjunct to pegylated IFN, with or without ribavirin. As a priority, they recommended research among selected genotype one patients unable to tolerate ribavirin.

This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.